2006 – OPPOSING EFFECTS OF DNMT3A AND TET2 CLONAL HEMATOPOIESIS ON ALZHEIMER'S DISEASE PATHOGENESIS

Clonal Hematopoiesis of Indeterminate Potential (CHIP), a phenomenon in which a single hematopoietic stem cell (HSC) disproportionately contributes to the peripheral blood, is associated with an increased likelihood of developing many age-associated diseases. However, the connection to neurodegenerative diseases, such as Alzheimer's Disease (AD) is less clear. Prior studies have established that inflammation plays a central role in AD pathogenesis and mounting evidence suggests systemic inflammatory signals can be transmitted to the CNS, where they may play a direct role in microglia activation and plaque clearance. Here we investigated the role of the two most commonly mutated CHIP-associated genes, Dnmt3a and Tet2, in the pathogenesis of Alzheimer's Disease. We transplanted 5xFAD transgenic mice predisposed to develop familial AD with Dnmt3a-/-, Tet2-/- or wildtype (WT) bone marrow (BM). Mice were then challenged weekly with LPS to mimic systemic chronic inflammation seen in aging. 5xFAD mice transplanted with Dnmt3a-/- BM showed signs of exacerbated AD, including increased cognitive impairment and decreased microglia activation compared to those transplanted with WT BM. Mice transplanted with Dnmt3a-/- BM also had fewer peripheral immune cells infiltrating the brain. In contrast, 5xFAD mice transplanted with Tet2-/- BM showed improved cognitive status, increased amyloid plaque clearance and increased microglia activation, while having a higher percentage of activated infiltrating myeloid cells within the brain compared to WT controls. Our data suggest that Dnmt3a and Tet2 mutations impact peripheral immune cell infiltration leading to changes in microglia activation and AD pathogenesis. Overall, our study of CHIP and AD marks the first report in which Dnmt3a and Tet2, which have opposite roles in DNA methylation, induce opposing effects on disease progression.